Adrenergic receptors mediate physiological responses to the catecholamines, norepinephrine and epinephrine, and are members of the superfamily of G protein-coupled receptors having seven transmembrane domains.
These receptors, which are divided pharmacologically into α-1, α-2 and β-adrenergic receptor types, are involved in diverse physiological functions including functions of the cardiovascular and central nervous systems. The α-adrenergic receptors mediate excitatory and inhibitory functions: α-1 adrenergic receptors are typically excitatory post-synaptic receptors which generally mediate responses in an effector organ, while α-2 adrenergic receptors are located postsynaptically as well as presynaptically, where they inhibit release of neurotransmitters. The α-adrenergic receptors also mediate vascular constriction.
α-2 adrenergic receptors are presently classified into three subtypes based on their pharmacological and molecular characterization: α-2A/D (α-2A in human and α-2D in rat); α-2B; and α-2C (Bylund et al., Pharmacol. Rev. 46:121-136 (1994); and Hein and Kobilka, Neuropharmacol. 34:357-366 (1995)). The α-2A, α-2B, and α-2C subtypes appear to regulate arterial and/or venular contraction in some vascular beds, and the α-2A and α-2C subtypes also mediate feedback inhibition of norepinephrine release from sympathetic nerve endings.
A human eye has a lot of α-2 adrenergic receptors. Agonists of these receptors may have an effect on an eye's appearance by causing lumen size reduction of α-2 receptor populated arterioles and, particularly, terminal arterioles. This may result in vasoconstriction, and more particularly microvessel lumen size reduction, which in turn may increase the per unit surface area degree of microvessel constriction, and therefore, improve cosmetic appearance of eyes. Whiter eyes are traditionally a societal symbol of natural healthy eyes, and excellent overall hygiene and health.
While some compounds may be agonists of both α-1 and α-2 receptors, there are many compounds which have selective α-2 agonist activity, meaning that they preferentially bind to α-2 adrenergic receptors. They include brimonidine (which has been used for lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension), guanfacine (which has been used to control high blood pressure), dexmedetomidine (which has been used as a sedative, analgesic, sympatholytic and anxiolytic), and methyl dopa (which has been used as a centrally acting adrenergic antihypertensive).
However, selective α-2 adrenergic receptor agonists, when used at conventional doses of 0.1% or higher, are associated with a number of undesirable side effects, such as rebound hyperemia. These effects may be associated with a “cross-over” stimulation of α-1 adrenergic receptors, as α-2 selectivity is a ratio of α-2/α-1 receptor activity.
Thus, there is a need for new compositions and methods that would improve cosmetic appearance of eyes by achieving eye whitening with reduced or eliminated side effects.